4.1. Therapeutic indications

Lojuxta is indicated as an adjunct to a low‑fat diet and other lipid‑lowering medicinal products with or without low density lipoprotein (LDL) apheresis in adult patients with homozygous familial hypercholesterolaemia (HoFH).

Genetic confirmation of HoFH should be obtained whenever possible. Other forms of primary hyperlipoproteinemia and secondary causes of hypercholesterolaemia (e.g., nephrotic syndrome, hypothyroidism) must be excluded.

4.2. Posology and method of administration

Treatment with Lojuxta should be initiated and monitored by a physician experienced in the treatment of lipid disorders.

Posology

The recommended starting dose is 5 mg once daily. After 2 weeks the dose may be increased, based on acceptable safety and tolerability, to 10 mg and then, at a minimum of 4‑week intervals, to 20 mg, 40 mg, and to the maximum recommended dose of 60 mg (see section 4.8).

The dose should be escalated gradually to minimise the incidence and severity of gastrointestinal adverse reactions and aminotransferase elevations.

Administration with food may increase exposure to lomitapide. It should be taken on an empty stomach, at least 2 hours after the evening meal because the fat content of a recent meal may adversely impact gastrointestinal tolerability.

The occurrence and severity of gastrointestinal adverse reactions associated with the use of Lojuxta decreases in the presence of a low fat diet. Patients should follow a diet supplying less than 20% of energy from fat prior to initiating treatment, and should continue this diet during treatment. Dietary counselling should be provided.

Patients should avoid consumption of grapefruit juice (see sections 4.4 and 4.5).

For patients on a stable maintenance dose of Lojuxta who receive atorvastatin either:

• Separate the dose of the medicinal products by 12 hours

OR

• Decrease the dose of Lojuxta by half.

Patients on 5 mg should remain on 5 mg.

Careful titration may then be considered according to LDL‑C response and safety/tolerability.

Upon discontinuation of atorvastatin the dose of Lojuxta should be up-titrated according to LDL‑C response and safety/tolerability.

For patients on a stable maintenance dose of Lojuxta who receive any other weak CYP3A4 inhibitor, separate the dose of the medicinal products (Lojuxta and the weak CYP3A4 inhibitor) by 12 hours.

Consider limiting the maximum dose of Lojuxta according to desired LDL-C response.

Exercise additional caution if administering more than 1 weak CYP3A4 inhibitor with Lojuxta.

Based on observations of decreased essential fatty acid and vitamin E levels in clinical studies, patients should take daily dietary supplements that provide 400 IU vitamin E and approximately 200 mg linoleic acid, 110 mg eicosapentaenoic acid (EPA), 210 mg alpha linolenic acid (ALA) and 80 mg docosahexaenoic acid (DHA) per day, throughout treatment with Lojuxta.

Special populations

Elderly population

There is limited experience with lomitapide in patients aged 65 years or older. Therefore, particular caution should be exercised in these patients.

Since the recommended dose regimen involves starting at the low end of the dosing range and escalating cautiously according to individual patient tolerability, no adjustment to the dosing regimen is recommended for the elderly.

Hepatic impairment

Lomitapide is contraindicated in patients with moderate or severe hepatic impairment including patients with unexplained persistent abnormal liver function tests (see sections 4.3 and 5.2).

Patients with mild hepatic impairment (Child‑Pugh A) should not exceed 40 mg daily.

Renal impairment

Patients with end‑stage renal disease receiving dialysis should not exceed 40 mg daily (see section 5.2).

Paediatric population

The safety and efficacy of lomitapide in children <18 years have not been established and the use of this medicinal product in children is therefore not recommended. No data are available.

Method of administration

Oral use.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Patients with moderate or severe hepatic impairment and those with unexplained persistent abnormal liver function tests (see section 4.2).

• Patients with a known significant or chronic bowel disease such as inflammatory bowel disease or malabsorption.

• Concomitant administration of >40 mg simvastatin (see section 4.5).

• Concomitant use of Lojuxta with strong or moderate cytochrome P450 (CYP) 3A4 inhibitors (e.g., antifungal azoles such as itraconazole, fluconazole,ketoconazole, voriconazole, posaconazole; macrolide antibiotics such as erythromycin or clarithromycin; ketolide antibiotics such as telithromycin; HIV protease inhibitors; the calcium channel blockers diltiazem and verapamil, and the anti-arrhythmic dronedarone [see section 4.5]).

• Pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

Liver enzyme abnormalities and liver monitoring

Lomitapide can cause elevations in the liver enzymes alanine aminotransferase [ALT] and aspartate aminotransferase [AST] and hepatic steatosis (see section 5.1). There have been no concomitant or subsequent clinically meaningful elevations in serum bilirubin, INR, or alkaline phosphatase. The extent to which lomitapide‑associated hepatic steatosis promotes the elevations in aminotransferase is unknown. The liver enzyme changes can occur at any time during therapy, but occur most often during dose escalation.

Although cases of hepatic dysfunction (elevated aminotransferase with increase in bilirubin or International Normalized Ratio [INR]) or hepatic failure have not been reported, there is concern that lomitapide could induce steatohepatitis, which can progress to cirrhosis over several years. The clinical studies supporting the safety and efficacy of lomitapide in HoFH would have been unlikely to detect this adverse outcome given their size and duration.

Monitoring of liver function tests

Measure ALT, AST, alkaline phosphatase, total bilirubin, gamma-glutamyl transferase (gamma-GT) and serum albumin before initiation of treatment with Lojuxta. The medicinal product is contraindicated in patients with moderate or severe hepatic impairment and those with unexplained persistent abnormal liver function tests. If the baseline liver‑related tests are abnormal, consider initiating the medicinal product after appropriate investigation by a hepatologist and the baseline abnormalities are explained or resolved.

During the first year, measure liver-related tests (ALT and AST, at a minimum) prior to each increase in dose or monthly, whichever occurs first. After the first year, do these tests at least every 3 months and before any increase in dose. Decrease the dose of Lojuxta if elevations of aminotransferase are observed and discontinue treatment for persistent or clinically significant elevations (see Table 1 for specific recommendations).

Dose modification based on elevated hepatic aminotransferases

Table 1 summarizes recommendations for dose adjustment and monitoring for patients who develop elevated aminotransferase during therapy with Lojuxta.

Table 1: Dose adjustment and monitoring for patients with elevated aminotransferases

ALT or AST

Treatment and monitoring recommendations*

≥3x and <5x Upper Limit of Normal (ULN)

• Confirm elevation with a repeat measurement within one week.

• If confirmed, reduce the dose and obtain additional liver-related tests if not already measured (such as alkaline phosphatase, total bilirubin, and INR).

• Repeat tests weekly and withhold dosing if there are signs of abnormal liver function (increase in bilirubin or INR), if aminotransferase levels rise above 5x ULN, or if aminotransferase levels do not fall below 3x ULN within approximately 4 weeks. Refer patients with persistent elevations in aminotransferase >3x ULN to a hepatologist for further investigation.

• If resuming Lojuxta after aminotransferase levels resolve to <3x ULN, consider reducing the dose and monitor liver-related tests more frequently.

≥5x ULN

• Withhold dosing and obtain additional liver-related tests if not already measured (such as alkaline phosphatase, total bilirubin, and INR). If aminotransferase levels do not fall below 3x ULN within approximately 4 weeks refer the patient to a hepatologist for further investigation.

• If resuming Lojuxta after aminotransferase levels resolve to <3x ULN, reduce the dose and monitor liver-related tests more frequently.

*Recommendations based on an ULN of approximately 30-40 international units/L.

If aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, abdominal pain, fever, jaundice, lethargy, flu-like symptoms), increases in bilirubin ≥2x ULN, or active liver disease, discontinue treatment with Lojuxta and refer the patient to a hepatologist for further investigation.

Reintroduction of treatment may be considered if the benefits are considered to outweigh the risks associated with potential liver disease.

Hepatic steatosis and risk of progressive liver disease

Consistent with the mechanism of action of lomitapide, most treated patients exhibited increases in hepatic fat content. In an open-label Phase 3 study, 18 of 23 patients with HoFH developed hepatic steatosis (hepatic fat >5.56%) as measured by nuclear magnetic resonance spectroscopy (MRS) (see section 5.1). The median absolute increase in hepatic fat was 6% after both 26 weeks and 78 weeks of treatment, from 1% at baseline, measured by MRS. Hepatic steatosis is a risk factor for progressive liver disease including steatohepatitis and cirrhosis. The long term consequences of hepatic steatosis associated with lomitapide treatment are unknown. Clinical data suggest that hepatic fat accumulation is reversible after stopping treatment with Lojuxta, but whether histological sequelae remain is unknown, especially after long-term use.

Monitoring for evidence of progressive liver disease.

Regular screening for steatohepatitis/fibrosis should be performed at baseline and on an annual basis using the following imaging and biomarker evaluations:

• Imaging for tissue elasticity, e.g. Fibroscan, acoustic radiation force impulse (ARFI), or magnetic resonance (MR) elastography

• Gamma-GT and serum albumin to detect possible liver injury

• At least one marker from each of the following categories:

• High sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), CK-18 Fragment, NashTest (liver inflammation)

• Enhanced Liver Fibrosis (ELF) panel, Fibrometer, AST/ALT ratio, Fib-4 score, Fibrotest (liver fibrosis)

The performance of these tests and their interpretation should involve collaboration between the treating physician and the hepatologist. Patients with results suggesting the presence of steatohepatitis or fibrosis should be considered for liver biopsy.

If a patient has biopsy-proven steatohepatitis or fibrosis, the benefit-risk should be reassessed and treatment stopped if necessary.

Dehydration

Post‑marketing reports of dehydration and hospitalisation in patients treated with lomitapide have been reported. Patients treated with lomitapide should be advised of the potential risk of dehydration in relation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.

Concomitant use of CYP3A4 inhibitors

Lomitapide appears to be a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27‑fold. Concomitant use of moderate or strong CYP3A4 inhibitors with Lojuxta is contraindicated (see section 4.3). In the lomitapide clinical studies, one patient with HoFH developed markedly elevated aminotransferase (ALT 24x ULN, AST 13x ULN) within days of initiating the strong CYP3A4 inhibitor clarithromycin. If treatment with moderate or strong CYP3A4 inhibitors is unavoidable, Lojuxta should be stopped during the course of treatment.

Weak CYP3A4 inhibitors are expected to increase the exposure of lomitapide when taken simultaneously. When administered with atorvastatin, the dose of Lojuxta should either be taken 12 hours apart or be decreased by half (see section 4.2). The dose of Lojuxta should be administered 12 hours apart from any other weak CYP3A4 inhibitor.

Concomitant use of CYP3A4 inducers

Medicinal products that induce CYP3A4 would be expected to increase the rate and extent of metabolism of lomitapide. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.

Co-administration of a CYP3A4 inducer is expected to reduce the effect of lomitapide. Any impact on efficacy is likely to be variable. When co‑administering CYP3A4 inducers (i.e. aminoglutethimide, nafcillin, non‑nucleoside reverse transcriptase inhibitors, phenobarbital, rifampicin, carbamazepine, pioglitazone, glucocorticoids, modafinil and phenytoin) with Lojuxta, the possibility of a drug‑drug interaction affecting efficacy should be considered. The use of St. John's Wort should be avoided with Lojuxta.

It is recommended to increase the frequency of LDL‑C assessment during such concomitant use and consider increasing the dose of Lojuxta to ensure maintenance of the desired level of efficacy if the CYP3A4 inducer is intended for chronic use. On withdrawal of a CYP3A4 inducer, the possibility of increased exposure should be considered and a reduction in the dose of Lojuxta may be necessary.

Concomitant use of HMG‑CoA reductase inhibitors ('statins')

Lomitapide increases plasma concentrations of statins. Patients receiving Lojuxta as adjunctive therapy to a statin should be monitored for adverse events that are associated with the use of high doses of statins. Statins occasionally cause myopathy. In rare cases, myopathy may take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and can lead to fatality. All patients receiving lomitapide in addition to a statin should be advised of the potential increased risk of myopathy and told to report promptly any unexplained muscle pain, tenderness, or weakness. Doses of simvastatin >40 mg should not be used with Lojuxta (see section 4.3).

Grapefruit juice

Grapefruit juice must be omitted from the diet while patients are treated with Lojuxta.

Risk of supratherapeutic or subtherapeutic anticoagulation with coumarin based anticoagulants

Lomitapide increases the plasma concentrations of warfarin. Increases in the dose of Lojuxta may lead to supratherapeutic anticoagulation, and decreases in the dose may lead to subtherapeutic anticoagulation. Difficulty controlling INR contributed to early discontinuation from the Phase 3 study for one of five patients taking concomitant warfarin. Patients taking warfarin should undergo regular monitoring of the INR, especially after any changes in the dose of Lojuxta. The dose of warfarin should be adjusted as clinically indicated.

Use of alcohol

Alcohol may increase levels of hepatic fat and induce or exacerbate liver injury. In the Phase 3 study, 3 of 4 patients with ALT elevations >5x ULN reported alcohol consumption beyond the limits recommended in the protocol. The use of alcohol during lomitapide treatment is not recommended.

Hepatotoxic agents

Caution should be exercised when Lojuxta is used with other medicinal products known to have potential for hepatotoxicity, such as isotretinoin, amiodarone, acetaminophen (>4 g/day for ≥3 days/week), methotrexate, tetracyclines, and tamoxifen. The effect of concomitant administration of lomitapide with other hepatotoxic medicine is unknown. More frequent monitoring of liver‑related tests may be warranted.

Reduced absorption of fat‑soluble vitamins and serum fatty acids

Given its mechanism of action in the small intestine, lomitapide may reduce the absorption of fat‑soluble nutrients. In the Phase 3 study, patients were provided daily dietary supplements of vitamin E, linoleic acid, ALA, EPA and DHA. In this study, the median levels of serum vitamin E, ALA, linoleic acid, EPA, DHA, and arachidonic acid decreased from baseline to Week 26 but remained above the lower limit of the reference range. Adverse clinical consequences of these reductions were not observed with lomitapide treatment of up to 78 weeks. Patients treated with Lojuxta should take daily supplements that contain 400 international units vitamin E and approximately 200 mg linoleic acid, 210 mg ALA, 110 mg EPA, and 80 mg DHA.

Contraception measures in women of child‑bearing potential

Before initiating treatment in women of child‑bearing potential, appropriate advice on effective methods of contraception should be provided, and effective contraception initiated. Patients taking oestrogen‑based oral contraceptives should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting (see section 4.5). Oestrogen‑containing oral contraceptives are weak CYP3A4 inhibitors (see section 4.2).

Patients should be advised to immediately contact their physician and stop taking Lojuxta if they become pregnant (see section 4.6).

Lactose

Lojuxta contains lactose. Patients with rare hereditary problems of galactose intolerance, total‑lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on lomitapide and other forms of interaction

Table 2: Interactions between Lojuxta and other medicinal products and other forms of interaction

Medicinal products

Effects on lomitapide levels

Recommendation concerning co‑administration with Lojuxta

Inhibitors of CYP3A4

When lomitapide 60 mg was co‑administered with ketoconazole 200 mg twice daily, a strong inhibitor of CYP3A4, lomitapide AUC increased approximately 27‑fold and Cmax increased approximately 15‑fold.

Interactions between moderate CYP3A4 inhibitors and lomitapide have not been studied.

Moderate CYP3A4 inhibitors are predicted to have a substantial impact on lomitapide's pharmacokinetics. Concomitant use of moderate CYP3A4 inhibitors are expected to increase lomitapide exposure by 4‑10 fold based on the results of the study with the strong CYP3A4 inhibitor ketoconazole and on historical data for the model CYP3A4 probe midazolam.

Weak CYP3A4 inhibitors are expected to increase the exposure of lomitapide when taken simultaneously.

When lomitapide 20 mg was co‑administered simultaneously with atorvastatin, a weak CYP3A4 inhibitor, lomitapide AUC and Cmax increased approximately 2‑fold. When the dose of lomitapide was taken 12 hours apart from atorvastatin, no clinically meaningful increase in lomitapide exposure was observed.

When lomitapide 20 mg was co-administered simultaneously or 12 hours apart with ethinyl estradiol/norgestimate, a weak CYP3A4 inhibitor, no clinically meaningful increase in lomitapide exposure was observed.

Use of strong or moderate inhibitors of CYP3A4 is contraindicated with Lojuxta. If treatment with antifungal azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole, posaconazole); the antiarrhythmic dronedarone; macrolide antibiotics (e.g., erythromycin, clarithromycin); ketolide antibiotics (e.g., telithromycin); HIV protease inhibitors; the calcium channel blockers diltiazem and verapamil is unavoidable, therapy with Lojuxta should be suspended during the course of treatment (see sections 4.3 and 4.4).

Grapefruit juice is a moderate inhibitor of CYP3A4 and is expected to substantially increase exposure to lomitapide. Patients taking Lojuxta should avoid consumption of grapefruit juice.

When administered with atorvastatin, the dose of Lojuxta should either be taken 12 hours apart or be decreased by half (see section 4.2). The dose of Lojuxta should be taken 12 hours apart from any other concomitant weak CYP3A4 inhibitors. Examples of weak CYP3A4 inhibitors include: alprazolam, amiodarone, amlodipine, atorvastatin, azithromycin, bicalutamide, cilostazol, cimetidine, ciclosporin, clotrimazole, fluoxetine, fluvoxamine, fosaprepitant, ginkgo, goldenseal, isoniazid, ivacaftor, lacidipine, lapatinib, linagliptin, nilotinib, oestrogen‑containing oral contraceptives, pazopanib, peppermint oil, propiverine, ranitidine, ranolazine, roxithromycin, Seville oranges, tacrolimus, ticagrelor and tolvaptan. This list is not intended to be comprehensive and prescribers should check the prescribing information of medicinal products to be co-administered with Lojuxta for potential CYP3A4 mediated interactions.

The effect of administration of more than one weak CYP3A4 inhibitor has not been tested, but the effect on the exposure of lomitapide is expected to be greater than for co-administration of the individual inhibitors with lomitapide.

Exercise additional caution if administering more than 1 weak CYP3A4 inhibitor with Lojuxta.

Inducers of CYP3A4

Medicines that induce CYP3A4 would be expected to increase the rate and extent of metabolism of lomitapide. Consequently, this would reduce the effect of lomitapide. Any impact on efficacy is likely to be variable.

When co-administering CYP3A4 inducers (i.e., aminoglutethimide, nafcillin, non-nucleoside reverse transcriptase inhibitors, phenobarbital, rifampicin, carbamazepine, pioglitazone, St John's Wort, glucocorticoids, modafinil and phenytoin) with Lojuxta, the possibility of a drug-drug interaction affecting efficacy should be considered. It is recommended to increase the frequency of LDL-C assessment during such concomitant use and consider increasing the dose of Lojuxta to ensure maintenance of the desired level of efficacy if the CYP3A4 inducer is intended for chronic use.

Bile acid sequestrants

Lomitapide has not been tested for interaction with bile acid sequestrants (resins such as colesevelam and cholestyramine).

Because bile acid sequestrants can interfere with the absorption of oral medicines, bile acid sequestrants should be taken at least 4 hours before or at least 4 hours after Lojuxta.

Effects of lomitapide on other medicinal products

HMG‑CoA Reductase Inhibitors (“Statins”): Lomitapide increases plasma concentrations of statins. When lomitapide 60 mg was administered to steady state prior to simvastatin 40 mg, simvastatin acid AUC and Cmax increased 68% and 57%, respectively. When lomitapide 60 mg was administered to steady state prior to atorvastatin 20 mg, atorvastatin acid AUC and Cmax increased 52% and 63%, respectively. When lomitapide 60 mg was administered to steady state prior to rosuvastatin 20 mg, rosuvastatin Tmax increased from 1 to 4 hours, AUC was increased 32%, and its Cmax was unchanged. The risk of myopathy with simvastatin is dose related. Use of Lojuxta is contraindicated in patients treated with high doses of simvastatin (>40 mg) (see sections 4.3 and 4.4).

Coumarin anticoagulants: When lomitapide 60 mg was administered to steady state and 6 days following warfarin 10 mg, INR increased 1.26‑fold. AUCs for R(+)‑warfarin and S(‑)‑warfarin increased 25% and 30%, respectively. Cmax for R(+)‑warfarin and S(‑)‑warfarin increased 14% and 15%, respectively. In patients taking coumarins (such as warfarin) and Lojuxta concomitantly, INR should be determined before starting Lojuxta and monitored regularly with dosage of coumarins adjusted as clinically indicated (see section 4.4).

Fenofibrate, niacin and ezetimibe: When lomitapide was administered to steady state prior to micronised fenofibrate 145 mg, extended release niacin 1000 mg, or ezetimibe 10 mg, no clinically significant effects on the exposure of any of these medicinal products were observed. No dose adjustments are required when co‑administered with Lojuxta.

Oral contraceptives: When lomitapide 50 mg was administered to steady state along with an oestrogen‑based oral contraceptive, no clinically meaningful or statistically significant impact on the pharmacokinetics of the components of the oral contraceptive (ethinyl estradiol and 17‑deacetyl norgestimate, the metabolite of norgestimate) was observed. Lomitapide is not expected to directly influence the efficacy of oestrogen based oral contraceptives; however diarrhoea and/or vomiting may reduce hormone absorption. In cases of protracted or severe diarrhoea and/or vomiting lasting more than 2 days, additional contraceptive measures should be used for 7 days after resolution of symptoms.

P‑gp substrates: Lomitapide inhibits P‑gp in vitro, and may increase the absorption of P‑gp substrates. Coadministration of Lojuxta with P gp substrates (such as aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan) may increase the absorption of P gp substrates. Dose reduction of the P gp substrate should be considered when used concomitantly with Lojuxta.

In vitro assessment of drug interactions: Lomitapide inhibits CYP3A4. Lomitapide does not induce CYPs 1A2, 3A4, or 2B6, and does not inhibit CYPs 1A2, 2B6, 2C9, 2C19, 2D6, or 2E1. Lomitapide is not a P‑gp substrate but does inhibit P‑gp. Lomitapide does not inhibit breast cancer resistance protein (BCRP).

4.6. Fertility, pregnancy and lactation

Use in women of child‑bearing potential

Before initiating treatment in women of child‑bearing potential, the absence of pregnancy should be confirmed, appropriate advice on effective methods of contraception provided, and effective contraception initiated. Patients taking oestrogen‑based oral contraceptives should be advised about possible loss of effectiveness due to diarrhoea and/or vomiting. Additional contraceptive measures should be used until resolution of symptoms (see section 4.5).

Pregnancy

Lojuxta is contraindicated during pregnancy. There are no reliable data on its use in pregnant women. Animal studies have shown developmental toxicity (teratogenicity, embryotoxicity, see section 5.3). The potential risk for humans is unknown.

Breast‑feeding

It is not known whether lomitapide is excreted into human milk. Because of the potential for adverse effects based on findings in animal studies with lomitapide (see section 5.3), a decision should be made whether to discontinue breast‑feeding or discontinue the medicinal product, taking into account the importance of the medicinal product to the mother.

Fertility

No adverse effects on fertility were observed in male and female rats administered lomitapide at systemic exposures (AUC) estimated to be 4 to 5 times higher than in humans at the maximum recommended human dose (see section 5.3).

4.7. Effects on ability to drive and use machines

Lojuxta has minor influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most serious adverse reactions during treatment were liver aminotransferase abnormalities (see section 4.4).

The most common adverse reactions were gastrointestinal effects. Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the Phase 3 clinical study. Diarrhoea occurred in 79% of patients, nausea in 65%, dyspepsia in 38%, and vomiting in 34%. Other reactions reported by at least 20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation, and flatulence. Gastrointestinal adverse reactions occurred more frequently during the dose escalation phase of the study and decreased once patients established the maximum tolerated dose of lomitapide.

Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the Phase 3 clinical study, with the most common being diarrhoea (4 patients, 14%); vomiting (3 patients, 10%); and abdominal pain, distension, and/or discomfort (2 patients, 7%). Gastrointestinal reactions contributed to the reasons for early discontinuation from the study for 4 (14%) patients.

The most commonly reported adverse reactions of severe intensity were diarrhoea (4 subjects, 14%), vomiting (3 patients, 10%), and abdominal distension and ALT increased (2 subjects each, 7%).

Tabulated list of adverse reactions

Frequency of the adverse reactions is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 3 lists all adverse reactions reported across the 35 patients treated in the Phase 2 Study UP1001 and in the Phase 3 Study UP1002/AEGR‑733‑005 or its extension study AEGR‑733‑012.

Table 3: Frequency of adverse reactions in HoFH patients

System Organ Class

Frequency

Adverse reaction

Infections and infestations

Common

Gastroenteritis

Metabolism and nutrition disorders

Very common

Decreased appetite

Not known

Dehydration

Nervous system disorders

Common

Dizziness

Headache

Migraine

Gastrointestinal disorders

Very common

Diarrhoea

Nausea

Vomiting

Abdominal discomfort

Dyspepsia

Abdominal pain

Abdominal pain upper

Flatulence

Abdominal distension

Constipation

Common

Gastritis

Rectal tenesmus

Aerophagia

Defaecation urgency

Eructation

Frequent bowel movements

Gastric dilatation

Gastric disorder

Gastrooesophageal reflux disease

Haemorrhoidal haemorrhage

Regurgitation

Hepatobiliary disorders

Common

Hepatic steatosis

Hepatotoxicity

Hepatomegaly

Skin and subcutaneous tissue disorders

Common

Ecchymosis

Papule

Rash erythematous

Xanthoma

Not known

Alopecia

Musculoskeletal and connective tissue disorders

Not known

Myalgia

General disorders and administration site conditions

Common

Fatigue

Investigations

Very common

Alanine aminotransferase increased

Aspartate aminotransferase increased

Weight decreased

Common

International normalised ratio increased

Blood alkaline phosphatase increased

Blood potassium decreased

Carotene decreased

International normalised ratio abnormal

Liver function test abnormal

Prothrombin time prolonged

Transaminases increased

Vitamin E decreased

Vitamin K decreased

Table 4 lists all adverse reactions for subjects who received lomitapide monotherapy (N=291) treated in Phase 2 studies in subjects with elevated LDL‑C (N=462).

Table 4: Frequency of adverse reactions in elevated LDL‑C patients

System Organ Class

Frequency

Adverse reaction

Infections and infestations

Uncommon

Gastroenteritis

Gastrointestinal infection

Influenza

Nasopharyngitis

Sinusitis

Blood and lymphatic system disorders

Uncommon

Anaemia

Metabolism and nutrition disorders

Common

Decreased appetite

Uncommon

Dehydration

Increased appetite

Nervous system disorders

Uncommon

Paraesthesia

Somnolence

Eye disorders

Uncommon

Eye swelling

Ear and labyrinth disorders

Uncommon

Vertigo

Respiratory, thoracic and mediastinal disorders

Uncommon

Pharyngeal lesion

Upper-airway cough syndrome

Gastrointestinal disorders

Very common

Diarrhoea

Nausea

Flatulence

Common

Abdominal pain upper

Abdominal distension

Abdominal pain

Vomiting

Abdominal discomfort

Dyspepsia

Eructation

Abdominal pain lower

Frequent bowel movements

Uncommon

Dry mouth

Faeces hard

Gastrooeosophageal reflux disease

Abdominal tenderness

Epigastric discomfort

Gastric dilatation

Haematemesis

Lower gastrointestinal haemorrhage

Reflux oesophagitis

Hepatobiliary disorders

Uncommon

Hepatomegaly

Skin and subcutaneous tissue disorders

Uncommon

Blister

Dry skin

Hyperhidrosis

Musculoskeletal and connective tissue disorders

Common

Muscle spasms

Uncommon

Arthralgia

Myalgia

Pain in extremity

Joint swelling

Muscle twitching

Renal and urinary disorders

Uncommon

Haematuria

General disorders and administrative site conditions

Common

Fatigue

Asthenia

Uncommon

Chest pain

Chills

Early satiety

Gait disturbance

Malaise

Pyrexia

Investigations

Common

Alanine aminotransferase increased

Aspartate aminotransferase increased

Hepatic enzyme increased

Liver function test abnormal

Neutrophil count decreased

White blood cell count decreased

Uncommon

Weight decreased

Blood bilirubin increased

Gamma-glutamyltransferase increased

Neutrophil percentage increased

Protein urine

Prothrombin time prolonged

Pulmonary function test abnormal

White blood cell count increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

There is no specific treatment in the event of overdose. In the event of overdose, the patient should be treated symptomatically and supportive measures instituted as required. Liver related tests should be monitored. Haemodialysis is unlikely to be beneficial given that lomitapide is highly protein bound.

In rodents, single oral doses of lomitapide ≥600 times higher than the maximum recommended human dose (1 mg/kg) were well tolerated. The maximum dose administered to human subjects in clinical studies was 200 mg as a single dose; there were no adverse reactions.